Intestinal IL-33 promotes platelet activity for neutrophil recruitment during acute inflammation

Blood ◽  
2021 ◽  
Author(s):  
Zuojia Chen ◽  
Jialie Luo ◽  
Jian Li ◽  
Girak Kim ◽  
C. Andrew Stewart ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Acute Inflammation ◽  
Intestinal Inflammation ◽  
Endotoxic Shock ◽  
Whole Body ◽  
Intestinal Epithelial ◽  
Platelet Activity ◽  
Interleukin 33 ◽  
Neutrophil Extravasation

The peripheral serotonin (5-HT) is mainly generated from the gastrointestinal tract, and taken up and stored by platelets in the circulation. While the gut is recognized as a major immune organ, how intestinal local immune responses control whole body physiology via 5-HT is yet unclear. Here, we show that intestinal inflammation enhances systemic platelet activation and blood coagulation. Intestinal epithelium damage induces the elevated level of alarm cytokine interleukin-33 (IL-33), leading to platelet activation via promoting gut-derived 5-HT release. More importantly, we found that loss of intestinal epithelial-derived IL-33 dampens peripheral 5-HT level, resulting in compromised platelet activation and hemostasis. Functionally, intestinal IL-33 contributes to the recruitment of neutrophils to the sites of acute inflammation by enhancing platelet activities. Genetical deletion of intestinal IL-33 or neutralization of peripheral IL-33, protects the animals from lipopolysaccharide endotoxic shock owing to attenuated neutrophil extravasation. Therefore, our data establish a distinct role of intestinal IL-33 in activating platelet by promoting 5-HT release for systemic physiology and inflammation.

scholarly journals Neuropeptide Y (NPY) promotes inflammation-induced tumorigenesis by enhancing epithelial cell proliferation

2017 ◽  
Vol 312 (2) ◽  
pp. G103-G111 ◽  
Author(s):  
Sabrina Jeppsson ◽  
Shanthi Srinivasan ◽  
Bindu Chandrasekharan
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Neuropeptide Y ◽  
Intestinal Inflammation ◽  
Enteric Neurons ◽  
Intestinal Epithelial ◽  
Epithelial Proliferation ◽  
Proliferation And Apoptosis

We have demonstrated that neuropeptide Y (NPY), abundantly produced by enteric neurons, is an important regulator of intestinal inflammation. However, the role of NPY in the progression of chronic inflammation to tumorigenesis is unknown. We investigated whether NPY could modulate epithelial cell proliferation and apoptosis, and thus regulate tumorigenesis. Repeated cycles of dextran sodium sulfate (DSS) were used to model inflammation-induced tumorigenesis in wild-type (WT) and NPY knockout ( NPY−/−) mice. Intestinal epithelial cell lines (T84) were used to assess the effects of NPY (0.1 µM) on epithelial proliferation and apoptosis in vitro. DSS-WT mice exhibited enhanced intestinal inflammation, polyp size, and polyp number (7.5 ± 0.8) compared with DSS- NPY−/− mice (4 ± 0.5, P < 0.01). Accordingly, DSS-WT mice also showed increased colonic epithelial proliferation (PCNA, Ki67) and reduced apoptosis (TUNEL) compared with DSS- NPY−/− mice. The apoptosis regulating microRNA, miR-375, was significantly downregulated in the colon of DSS-WT (2-fold, P < 0.01) compared with DSS- NPY−/−-mice. In vitro studies indicated that NPY promotes cell proliferation (increase in PCNA and β-catenin, P < 0.05) via phosphatidyl-inositol-3-kinase (PI3-K)-β-catenin signaling, suppressed miR-375 expression, and reduced apoptosis (increase in phospho-Bad). NPY-treated cells also displayed increased c-Myc and cyclin D1, and reduction in p21 ( P < 0.05). Addition of miR-375 inhibitor to cells already treated with NPY did not further enhance the effects induced by NPY alone. Our findings demonstrate a novel regulation of inflammation-induced tumorigenesis by NPY-epithelial cross talk as mediated by activation of PI3-K signaling and downregulation of miR-375. NEW & NOTEWORTHY Our work exemplifies a novel role of neuropeptide Y (NPY) in regulating inflammation-induced tumorigenesis via two modalities: first by enhanced proliferation (PI3-K/pAkt), and second by downregulation of microRNA-375 (miR-375)-dependent apoptosis in intestinal epithelial cells. Our data establish the existence of a microRNA-mediated cross talk between enteric neurons producing NPY and intestinal epithelial cells, and the potential of neuropeptide-regulated miRNAs as potential therapeutic molecules for the management of inflammation-associated tumors in the gut.

scholarly journals Thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease

2008 ◽  
Vol 105 (46) ◽  
pp. 17931-17936 ◽  
Author(s):  
Danyvid Olivares-Villagómez ◽  
Yanice V. Mendez-Fernandez ◽  
Vrajesh V. Parekh ◽  
Saif Lalani ◽  
Tiffaney L. Vincent ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Genetic Model ◽  
Critical Role ◽  
Intraepithelial Lymphocytes ◽  
Lymphocyte Function ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel

Intestinal intraepithelial lymphocytes (IEL) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. However, this phenotype also implies that IEL must be highly controlled to prevent misdirected immune reactions. It has been suggested that IEL are regulated through the interaction of the CD8αα homodimer with the thymus leukemia (TL) antigen expressed by intestinal epithelial cells. We have generated and characterized mice genetically-deficient in TL expression. Our findings show that TL expression has a critical role in maintaining IEL effector functions. Also, TL deficiency accelerated colitis in a genetic model of inflammatory bowel disease. These findings reveal an important regulatory role of TL in controlling IEL function and intestinal inflammation.

scholarly journals Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism

2018 ◽  
Vol 115 (43) ◽  
pp. 11036-11041 ◽  
Author(s):  
Yasuharu Nagahama ◽  
Mayuko Shimoda ◽  
Guoliang Mao ◽  
Shailendra Kumar Singh ◽  
Yuuki Kozakai ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Body Weight Loss ◽  
Purine Metabolism ◽  
Intestinal Epithelial ◽  
Beneficial Effects ◽  
Epithelial Regeneration ◽  
Mtorc1 Signaling ◽  
Inflammatory Bowel

Damage to intestinal epithelial cell (IEC) layers during intestinal inflammation is associated with inflammatory bowel disease. Here we show that the endoribonuclease Regnase-1 controls colon epithelial regeneration by regulating protein kinase mTOR (the mechanistic target of rapamycin kinase) and purine metabolism. During dextran sulfate sodium-induced intestinal epithelial injury and acute colitis, Regnase-1∆IEC mice, which lack Regnase-1 specifically in the intestinal epithelium, were resistant to body weight loss, maintained an intact intestinal barrier, and showed increased cell proliferation and decreased epithelial apoptosis. Chronic colitis and tumor progression were also attenuated in Regnase-1∆IEC mice. Regnase-1 predominantly regulates mTORC1 signaling. Metabolic analysis revealed that Regnase-1 participates in purine metabolism and energy metabolism during inflammation. Furthermore, increased expression of ectonucleotidases contributed to the resolution of acute inflammation in Regnase-1∆IEC mice. These findings provide evidence that Regnase-1 deficiency has beneficial effects on the prevention and/or blocking of intestinal inflammatory disorders.

scholarly journals Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

2018 ◽  
Vol 116 (3) ◽  
pp. 970-975 ◽  
Author(s):  
Yue Li ◽  
Marita Führer ◽  
Ehsan Bahrami ◽  
Piotr Socha ◽  
Maja Klaudel-Dreszler ◽  
...  
Keyword(s):  
Cell Death ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Loss Of Function ◽  
Monogenic Disorders ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Human Immune

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

scholarly journals IL-33 regulates gene expression in intestinal epithelial cells independently of its nuclear localization

2018 ◽  
Author(s):  
Zhengxiang He ◽  
Lili Chen ◽  
Glaucia C. Furtado ◽  
Sergio A. Lira
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Full Length ◽  
Nuclear Accumulation ◽  
List Type ◽  
Intestinal Epithelial ◽  
Regulated Gene Expression

AbstractIL-33 is a cytokine found in the extracellular space (mature IL-33) or in the cell nucleus (full-length IL-33). Nuclear accumulation of IL-33 has been reported in intestinal epithelial cells (IEC) during intestinal inflammation and cancer, but a functional role for this nuclear form remains unclear. To study the role of nuclear IL-33inIEC, we generated transgenic mice expressing full-length IL-33inthe intestinal epithelium (Vfl33mice). Expression of full-length IL-33 in the epithelium resulted in accumulation of IL-33 protein in the nucleus and secretion of IL-33. Over-expression of full-length IL-33 by IEC did not promote gut inflammation, but induced expression of genes in the IEC and lamina propria lymphocytes (LPL) that correlated negatively with genes expressed in inflammatory bowel diseases (IBD). Because the IL-33 receptor ST2 is expressed by IEC, there was the potential that both the mature and full-length forms could mediate this effect. To specifically interrogate the transcriptional role of nuclear IL-33,weintercrossed theVfl33mice with ST2-deficient mice. ST2 deficiency completely abrogated the transcriptional effects elicited by IL-33 expression, suggesting that the transcriptional effects of IL-33 on IEC are mediated by its mature, not its nuclear form.HighlightsExpression of full-length IL-33 in the epithelium resulted in accumulation of IL-33 protein in the nucleus and secretion of IL-33.Full-length IL-33 induced differential gene expression in IEC and LPL that was negatively associated with intestinal inflammatory diseasesIL-33 regulated gene expression in IEC via its extracellular (mature) form not via its nuclearform.

scholarly journals Role of HCA2 in Regulating Intestinal Homeostasis and Suppressing Colon Carcinogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhuoyue Li ◽  
Kayleen J. McCafferty ◽  
Robert L. Judd
Keyword(s):  
Immune Cells ◽  
Essential Role ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Physiological Role ◽  
Colon Carcinogenesis ◽  
Intestinal Epithelial ◽  
Intestinal Homeostasis ◽  
Exogenous Ligands

Hydroxycarboxylic acid receptor 2 (HCA2) is vital for sensing intermediates of metabolism, including β-hydroxybutyrate and butyrate. It also regulates profound anti-inflammatory effects in various tissues, indicating that HCA2 may serve as an essential therapeutic target for mediating inflammation-associated diseases. Butyrate and niacin, endogenous and exogenous ligands of HCA2, have been reported to play an essential role in maintaining intestinal homeostasis. HCA2, predominantly expressed in diverse immune cells, is also present in intestinal epithelial cells (IECs), where it regulates the intricate communication network between diet, microbiota, and immune cells. This review summarizes the physiological role of HCA2 in intestinal homeostasis and its pathological role in intestinal inflammation and cancer.

scholarly journals Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3670-3679 ◽  
Author(s):  
Guoying Zhang ◽  
Binggang Xiang ◽  
Anping Dong ◽  
Radek C. Skoda ◽  
Alan Daugherty ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Whole Body ◽  
No Donor ◽  
No Donors ◽  
Deficient Mice

AbstractNitric oxide (NO) stimulates cGMP synthesis by activating its intracellular receptor, soluble guanylyl cyclase (sGC). It is a currently prevailing concept that No and cGMP inhibits platelet function. However, the data supporting the inhibitory role of NO/sGC/cGMP in platelets have been obtained either in vitro or using whole body gene deletion that affects vessel wall function. Here we have generated mice with sGC gene deleted only in megakaryocytes and platelets. Using the megakaryocyte- and platelet-specific sGC-deficient mice, we identify a stimulatory role of sGC in platelet activation and in thrombosis in vivo. Deletion of sGC in platelets abolished cGMP production induced by either NO donors or platelet agonists, caused a marked defect in aggregation and attenuated secretion in response to low doses of collagen or thrombin. Importantly, megakaryocyte- and platelet-specific sGC deficient mice showed prolonged tail-bleeding times and impaired FeCl3-induced carotid artery thrombosis in vivo. Interestingly, the inhibitory effect of the NO donor SNP on platelet activation was sGC-dependent only at micromolar concentrations, but sGC-independent at millimolar concentrations. Together, our data demonstrate important roles of sGC in stimulating platelet activation and in vivo thrombosis and hemostasis, and sGC-dependent and -independent inhibition of platelets by NO donors.

scholarly journals Temporal induction of intestinal epithelial hypoxia-inducible factor-2α is sufficient to drive colitis

2019 ◽  
Vol 317 (2) ◽  
pp. G98-G107 ◽  
Author(s):  
Sumeet Solanki ◽  
Samantha N. Devenport ◽  
Sadeesh K. Ramakrishnan ◽  
Yatrik M. Shah
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Hypoxia Inducible Factor ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel

Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α is sufficient to exacerbate colitis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.

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